Type 2 diabetes (T2D) has become a major public health problem worldwide. Among the contributing environmental factors, changes in dietary patterns and physical activity are undoubtedly key causal factors. At the same time, there is growing evidence that exposure to endocrine disrupting chemicals (EDCs) widely existing in industrial products, including bisphenol A (BPA) and phthalates, might also play a role in the development of the disease. Proposed mechanisms mediating the latter include influences on adipogenesis, inflammation, oxidative stress, steroid-signaling, and hepatic and pancreatic function. In this competing renewal, we will examine the relationship between urinary BPA and phthalate metabolites and risk of T2D in the Nurses'Health Study (NHS). First morning spot urine samples were collected in 18,743 NHS participants between 1999 and 2001. Among these participants, we will conduct a nested case-control study including 850 incident T2D cases and 850 matched controls. The specific aims are: 1. To test the hypothesis that higher levels of urinary BPA and phthalate metabolites are associated with increased risk of T2D, independent of diabetes risk factors, including diet and lifestyle. A subsample of 113 women provided 3 morning spot urine samples over 3 years. We will use these repeated measures to assess the long-term variation and correct the observed relative risk estimates for random measurement error using methods previously developed by our group. 2. To test the hypothesis that increased levels of liver enzymes (fetuin-A, GGT, ALT) are associated with increased risk of T2D, independent of obesity, alcohol intake, and markers of inflammation. 3. To examine the interplay between liver enzymes and BPA/phthalates in relation to T2D risk. We will investigate whether the association between BPA and phthalates and T2D risk is mediated by GGT, ALT and fetuin-A activity. In addition, we will test the hypothesis that the detrimental effects of BPA or phthalates on T2D are stronger among those with liver dysfunction, as reflected by increased liver enzymes. The large well-defined prospective cohort with availability of detailed information on diet and lifestyle in combination with urine samples and sensitive measures of EDC exposure provides a unique and cost-effective opportunity to identify novel risk factors affecting the development of T2D. Findings from these studies can be used to motivate safer food and product manufacturing practices to contribute to the prevention of T2D. PUBLIC HEALTH RELEVANCE: There is growing evidence that exposure to endocrine disrupting chemicals (EDCs) widely existing in industrial products, including bisphenol A (BPA) and phthalates, may play a role in the development of diabetes. In this study, we will examine whether higher levels of urinary BPA and phthalate metabolites are associated with increased risk of diabetes in a large cohort study. In addition, we will test the hypothesis that the detrimental effects of BPA or phthalates on diabetes are stronger among those with liver dysfunction, as reflected by increased liver enzymes. Findings from this study can be used to motivate safer food and product manufacturing practices to contribute to the prevention of diabetes.